Triazine derivatives for the treatment of conditions associated with nicotinamide adenine dinucleotide phosphate oxidase

ABSTRACT

A compound of formula (I) for use in the treatment of a condition or disorder associated with nicotinamide adenine dinucleotide phosphate oxidase.

FIELD OF THE INVENTION

The present invention relates to triazine derivatives for use in thetreatment of a condition or disorder associated with nicotinamideadenine dinucleotide phosphate oxidase (Nox). More specifically, thepresent invention relates to triazine derivatives as Nox inhibitors foruse in the treatment of various diseases that are caused or driven byelevated Nox activity. In particular the invention relates to compoundshaving selectivity for Nox4.

BACKGROUND OF THE INVENTION

The definition of oxidative stress is an in vivo imbalance between theformation and elimination of reactive oxygen. Changes of the normalredox state in the cell or tissues can produce harmful radicals that maydamage components of the cellular machinery, including DNA, proteins andlipids. If the cellular components are chemically altered that causegenetic changes, this has generally been considered to promote formationof cancer or other serious diseases.

Sources of Oxygen Radicals—

Numerous in vivo generators of oxygen radicals (O₂ ⁻, H₂O₂ and OH⁻) thatpotentially can cause oxidative stress have been identified: complex Iand III in the mitochondria and NAD(P)H oxidase, xanthine oxidase,cytochromes P450, metal ions (cobalt, vanadium, chromium, copper andiron) and some organic compounds that can redox cycle.

General Antioxidants—

There also are numerous endogenously cellular antioxidants such assuperoxide dismutase (SOD), catalase, glutathione peroxidase,peroxiredoxins and sulfiredoxin. Vitamins provided by the food are alsoconsidered as an important part of the protection of the organism fromharmful oxygen radicals, and recent discovery of important antioxidantspresent in many sources of food has increased the arsenal ofantioxidants.

Antioxidants as Therapeutics—

It is very clear that some antioxidants can be helpful in preventingdiseases and promote health. What is much less clear is what type ofantioxidants can be used. Many of the antioxidants present in naturalfood are redox active. If these types of redox active substances areisolated and provided as complementary pharmaceuticals—this may end upbeing more harmful than helpful. Clinical trials have shown thatuntargeted application of antioxidants, which broadly scavenge oxygenradicals, are not only ineffective but may even be harmful. This wasillustrated in a study made with sixty-seven randomized trials with232,550 participants including healthy and patients with variousdiseases (Bjelakovic G, Nikolova D, Simonetti R G, Gluud C. CochraneDatabase Syst Rev. 2008 Jul. 16; (3):CD004183. Epub 2008 Jul. 16).

Thus general antioxidants that are redox active may actually be addingto the cellular damage, by mediating a harmful redox cycle. Othergeneral antioxidants will harmfully block normal cellular in vivoactivity necessary to maintain bodily function.

Source and Role of Reactive Oxygen—

What has become increasingly clear is that what is causing excessiveproduction and accumulation of reactive oxygen, in a number ofpathological conditions, such as inflammation, type 2 diabetes, diabetescomplications, polycystic ovary syndrome, stroke, detrimentalneurological conditions and cancer, is not generally leaking oxygenradicals such as complex I or III in the mitochondria—rather it isup-regulated powerful producers of oxygen radicals—that are part of thenormal cellular signal transduction system. Thus the definition ofoxidative stress need not be oxygen radicals that will irreversiblyalter DNA, protein or lipids, but instead increasingly interfere, if upregulated with “normal” signal transduction creating an imbalance on acellular level that eventually may alter other tissues and whole bodilyfunction. A typical example of this is the metabolic syndrome, connectedto vascular disease, diabetes 2, stroke, nephropathy, neuropathy, heartfailure and stroke with insulin resistance as the initiating factor(Reaven, “Role of insulin resistance in human disease”, Diabetes 37(12),1988). Insulin resistance in itself is also part of normal bodilyfunction as a tool to direct storage of energy selectively to a suitablereceiving organ. However, when metabolic changes occur, such as inoverfeeding, or other disturbances such as acromegaly with excess growthhormone production or malfunctioning leptin as in ob/ob-mice, this willinduce a harmful condition with an uncontrolled insulin resistance thatmay cause organ failure connected to the metabolic syndrome. The commondenominator to the uncontrolled insulin resistance is overproduction oflocal and systemic oxygen radicals (Houstis et al., Nature 440, 2006;Katakam et al., J cereb blood Flow Metab, 2012 Jan. 11).

One of the most interesting candidates for this overproduction is afamily of trans-membrane proteins (enzymes), referred to as NAD(P)Hoxidase (Nox). There are seven family members of Nox identified (Nox 1-5and Duox 1-2) that very often are being recognized as a major or keysource of reactive oxygen and that also play a major role in a number ofcellular events as part of the normal cellular signal transductionsystem, including proliferation (Brar et al., Am J Physiol Lung Cell MolPhysiol, 282, 2002), growth (Brar et al., Am J Physiol Cell Physiol,282, 2002), fibrosis (Grewal et al., Am J Physiol, 276, 1999), migration(Sundaresan et al., Science, 270, 1995), apoptosis (Lundqvist-Gustafssonet al., J Leukoc Biol, 65, 1999), differentiation (Steinbeck et al., JCell Physiol, 176, 1998), cytoskeletal rearrangement (Wu et al., JVirol, 78, 2004) and contraction (Rueckschloss et al., Exp Gerontol, 45,2010).

NADPH Oxidase and Disease—

Some genetic conditions with decreased NADPH oxidase activity have beenidentified—defect Nox2 decreases immunologic response to kill andneutralize microbial attacks (Chronic granulomatous disease)—defect Nox3in inner ear renders defective gravity perception and dual NAD(P)Hoxidase Duox2 having deficient enzymatic activity in the thyroid glandgives rise to hypothyroidism.

There is however a much larger list of publications that also seems togrow exponentially, that witness of strong evidence that increased Noxactivity is part of or even causative of a number of diseases (Lambeth JD, Review Article “Nox enzymes, ROS, and chronic disease: An example ofantagonistic pleiotropy”, Free Radical Biology & Medicine 43, 2007;Takac I et al., “The Nox Family of NADPH Oxidases: Friend or Foe of theVascular System”, Curr Hypertens Rep. 2011 Nov. 10; Montezano A C,“Novel Nox homologues in the vasculature: focusing on Nox4 and Nox5”,Clin Sci London 2011; Bedard K et al., “The Nox family of ROS-generatingNADPH oxidases: physiology and pathophysiology” Physiol Rev. 2007;Camici M et al., “Obesity-related glomerulopathy and podocyte injury: amini review”, Front Biosci 2012; Nabeebaccus A et al., “NADPH oxidasesand cardiac remodeling” Heart Fai Rev. 2011; Kuroda J et al., “NADPHoxidase and cardiac failure” J Cardiovasc Transl Res. 2010; Kuroda J etal., “NADPH oxidase 4 is a major source of oxidative stress in thefailing heart” Proc Natl Acad Sci USA 2010; Maejima Y et al.,“Regulation of myocardial growth and death by NADPH oxidase” J Mol CellCardiol. 2011; Barnes J L et al., “Myofibroblst differentiation duringfibrosis: role of NAD(P)H oxidases” Kidney international, 2011; AlisonCave “Selective targeting of NADPH oxidase for cardiovascularprotection” Current Opinion in Pharmacology 2009; Albert van der Vliet“Nox enzymes in allergic airway inflammation” Biochimica et BiophysicaActa 1810, 2011; Pendyala S et al., “Redox regulation of Nox proteins”Respiratory Physiology & Neurobiology 174, 2010; Nair D et al.,“Intermittent Hypoxia-Induced Cognitive Deficits Are Mediated by NADPHoxidase Activity in a Murine Model of Sleep Apnea” PLoS ONE, vol. 6,Issue 5, May 2011; Chia-Hung Hsieh et al., “NADPH oxidase Subunit4-Mediated Reactive Oxygen species Contribute to CyclingHypoxia-Promoted Tumor Progression in Glioblastoma Multiforme” PloS ONE,vol 6, issue 9, September 2011; Sedeek M et al., “Molecular mechanismsof hypertension: role of nox family NADPH oxidase” Current Opinion inNephrology and Hypertension 2009; Augusto C et al., “Novel Noxhomologues in the vasculature: focusing on Nox4 and Nox5” ClinicalScience 2011; Briones A M et al., “Differential regulation of Nox1, Nox2and Nox4 in vascular smooth muscle cells from WKY and SHR” Journal ofthe American Society of Hypertension 5:3, 2011).

It has been recently shown that the Nox enzymes and particularly Nox 4and NAD(P)H-oxidase are highly involved in pulmonary fibrosis. Thefunction of oxidative stress in fibrosis are well recognized (Kinnula VL, Fattman C L, Tan R J, Oury T D (2005) Oxidative stress in pulmonaryfibrosis: a possible role for redox modulatory therapy. Am J Respir CritCare Med 172:417-422), as there is a substantial and growing body ofevidence indicating that oxidative stress plays an important role in thepathological development of lung fibrosis as well as fibrosis inmultiple organ systems (Kuwano K, Nakashima N, Inoshima I, Hagimoto N,Fujita M, Yoshimi M, Maeyama T, Hamada N, Watanabe K, Hara N (2003)Oxidative stress in lung epithelial cells from patients with idiopathicinterstitial pneumonias. Eur Respir J 21:232-240). Thus, Nox enzymes andparticularly Nox4 appear to be involved also in lung infections, acutelung injury, pulmonary arterial hypertension, obstructive lungdisorders, fibrotic lung disease, and lung cancer.

NADPH Oxidase Isoenzymes, Similarities, Differences and Function—

All the seven isoenzymes of NADPH oxidase (identified) are similar inthe way of having NADPH and FAD binding site and six trans-membranedomains and in that they include two heme complexes. All the NADPHoxidase forms use the same basic mechanism to generate reactive oxygen,but the subcellular localizations and the modes of actions differsignificantly. The reactive oxygen species produced by the enzymaticNox-family are either superoxide O₂ ⁻ or hydrogen peroxide H₂O₂.

Nox1 and 2 are constitutively attached to p22phox and to activate theenzyme complex other components such as Rac, p47phox, p67phox arerequired for full Nox1 activity. Nox2 needs Rac, p40phox, p47phox andp67phox for full activation. Nox1 and 2 generate O₂ ⁻ when activated.

Nox3 also needs to assemble cytosolic proteins to be active (Cheng etal., J Biol Chem, 279(33), 2004).

Nox4 is also associated with p22phox, and is constitutively active inthis form. Nox4 activity is, however, regulated through expression—notthrough assembly or ligand activation, which distinguishes this isoformfrom other isoforms (Serrander et al., Biochem J. 406, 2007). Wheninduced, Nox4 is generally expressed at higher level than Nox1 and 2(Ago et al., Circulation, 109, 2004). Nox4 seems to mainly generate H₂O₂instead of O₂ ⁻ as the other Nox-variants (Takac et al., J. Biol. Chem.286, 2011). This makes this isoform unique because H₂O₂ has the abilityto cross membranes and thus to act at longer distance than O₂ ⁻ that hasa very short half-life.

Nox5, Doux1 and Doux2 are activated by Ca²¹ (De Deken, Wang et al., J.Biol Chem., 275(30), 2000).

Nox4 and Diseases—

The uniqueness of Nox4 in comparison to the other isoforms is alsoconnected to uniqueness as a therapeutic target as it seems to beinvolved in a number of different diseases when overexpressed.

Nox4 is ubiquitously expressed in many cell-types although at a very lowlevel until induced. It is, however mainly found in kidney, endothelialcells, adventitial fibroblasts, placenta, smooth muscle cells,osteoclasts and is the predominant Nox that is expressed in tumors(Chamseddine et al., Am J Physiol Heart Circ Physiol. 285, 2003; Ellmarket al., Cardiovasc Res. 65, 2005; Van Buul et al., Antioxid RedoxSignal. 7, 2005; Kawahara et al., BMC Evol Biol. 7, 2007; Krause et al.,Jpn J Infect is. 57(5), 2004; Griendling, Antioxid Redox Signal. 8(9),2006). It was found that Nox4 was overexpressed in the majority ofbreast cancer cell-lines and primary breast tumors. Overexpression ofNox4 in already transformed breast tumor cells showed increasedtumorigenicity, and Nox4 was here identified in the mitochondria. Nox4was suggested as a target to treat breast cancer (Graham et al., CancerBiol Ther 10(3), 2010).

Nox4 mediates oxidative stress and apoptosis caused by TNF-α in cerebralvascular endothelial cells (Basuroy et al., Am J Physiol Cell Physiolvol. 296, 2009). Its adverse effect following ischemic stroke is welldemonstrated in animal models and human tissue. Knockdown experiment, ofNox4, dramatically reduced the area of neuronal damage (Sedwick, PLosBiology, vol. 8 issue 9, 2010; Kleinschnitz et al., vol. 8 issue 9,2010)

It was demonstrated through knockdown and overexpression studies in bothmicrovascular and umbilical vein endothelial cells that increased Nox4activity plays an important role in proliferation and migration ofendothelial cells (Datla et al., Arterioscler Throm Vasc Biol. 27(11),2007). Initially it was believed that Nox2 was responsible for theangiogenic defects in diabetes but the focus has shifted more towardsNox4 (Zhang et al., PNAS, 107, 2010; Garriodo-Urbani et al., Plos One2011; Takac et al., Curr Hypertens Rep, 14, 2012). Nox4 play a key rolein epithelial cell death during development of lung fibrosis (Camesecchiet al., Antiox Redox Signal. 1:15(3), 2011).

It further was demonstrated that siRNA-mediated knockdown of Nox4significantly reduces NADPH oxidase activity in purified mitochondriafrom mesangial cells and kidney cortex. The knockdown blockedglucose-induced mitochondrial superoxide generation. It was suggestedthat Nox4 acts as a central mediator to oxidative stress that may leadto mitochondrial dysfunction and cell injury in diabetes (Block et al.,PNAS vol. 106, no. 34, 2009).

It also was demonstrated that Nox4 was systemically up-regulated atdiet-induced obesity in rats (Jiang, redox rep, 16(6), 2011).

Nox4 has been strongly connected to the pathology in failing hearts.(Nabeebaccus A et al. “NADPH oxidases and cardiac remodeling” Heart FaiRev. 2011; Kuroda J et al., “NADPH oxidase and cardiac failureCardiovasc Transl Res. 2010; Kuroda J et al., “NADPH oxidase 4 is amajor source of oxidative stress in the failing heart” Proc Natl AcadSci USA 2010). A connection between increased mitochondrial Nox4activity and dysfunction of “the aging heart” has been suggested(Tetsuro Ago et al., AGING, December 2010, vol. 2 No 12).

Extracellular matrix accumulation contributes to the pathology ofchronic kidney disease. The growth factor IGF-I activity is a majorcontributor to this process and Nox4 is a mediator in this process (Newet al., Am J Physiol Cell Physiol. 302(1), 2012). The connection betweenchronic activation of the renin-angiotensin and the progression ofkidney damage system is well established with Nox4 and Angiotensin II ascollaborators in this process (Chen et al., Mol Cell Biol. 2012).

From the above, it thus appears that the Nox enzymes have severalfunctions in the living body, and that they may also be involved invarious disorders. Examples of such diseases and disorders arecardiovascular disorders, respiratory disorders, metabolism disorders,endocrine disorders, skin disorders, bone disorders, neuroinflammatoryand/or neurodegenerative disorders, kidney diseases, reproductiondisorders, diseases affecting the eye and/or the lens and/or conditionsaffecting the inner ear, inflammatory disorders, liver diseases, pain,cancers, allergic disorders, traumatisms, such as traumatic head injury,septic, hemorrhagic and anaphylactic shock, diseases or disorders of thegastrointestinal system, angiogenesis, angiogenesis-dependentconditions. It also appears that especially Nox4 has been found to beinvolved in such disorders. Consequently, it is considered thatcompounds capable of inhibiting Nox, and in particular compounds capableof selectively inhibiting Nox4, would be of great interest for use inthe treatment of diseases and disorders involving Nox enzymes, and inparticular Nox4.

Several patent applications from GenKyoTex SA relate to various pyrazoloand pyrazoline derivatives for use as Nox inhibitors. Thus, PCTapplications WO 2010/035217, WO 2010/035219, WO 2010/035220, WO2010/035221, WO 2011/036651, WO2011/101804 and WO2011/101805, describeseveral conditions and disorders related to Nox and provide referencesto various sources of literature on the subject. The informationcontained in said applications and in the literature referred to thereinis incorporated herein by reference.

As noted herein above, Nox4 is involved in stroke, among other diseases.Stroke is the second leading cause of death worldwide and survivalsoften are disabled with serious cognitive difficulties affecting sociallife as well as the ability to perform work. In addition to thesuffering of the patients and the close relatives this also is extremelycostly to society and the healthcare system. Without new efficienttreatment of stroke patients, the cost to care for stroke victims duringthe next 45 years will exceed $2.2 trillion in the US only.

Stroke is classified into two major categories. Ischemic that causesinterruption of blood supply and hemorrhagic that results from ruptureof a blood vessel. Both induce rapid loss of brain function caused bydisturbances in blood supply. Ischemic stroke is by far the most commonform accounting for 87% of the cases, while 9% are due to intracerebralhemorrhage and the remaining 4% are due to subarachnoid hemorrhage.

The pathophysiology of ischemic stroke is complex and the patientrecovery is dependent on the length in time that neuronal tissues aredeprived of blood supply. Brain tissues deprived of oxygen for more thanthree hours will be irreversibly damaged. The pathophysiology includesexcitotoxicity mechanisms, inflammatory pathways, oxidative damage,ionic imbalances, apoptosis, angiogenesis and endogenous neuronprotection. Additionally when white blood cells re-enter a previouslyhypo perfused region via returning blood, they can occlude smallvessels, producing additional ischemia.

Different strategies to manage stroke are; to identify risk groups forpreventive treatment; development, implantation and dissemination ofevidence-based clinical practice guidelines in order to set a standardfor stroke management through the continuum of care with early treatmentthat is fundamental to improve the outcome following an ischemic strokeattack. One of two approved treatments today is IV administration oftissue plasminogen activator (tPA) that will induce thrombolysis, whichmay remove the clot and restore blood supply to the brain tissue. Theother method is to mechanically remove the clot, to restore bloodsupply. Other approaching methods are in early phase research and somein clinical trials. New potential therapies of interest includeadministration of neuroprotective agents, cooling of the ischemic brainand the use of stents to revasculate occluded arteries.

Thus, a method of treatment an ischemic stroke attack generallycomprises removing mechanical hinders (blood clots) from the blood flow,e.g. by intravenous administration of tissue plasminogen activator(tPA). It is thought that combining the removal of mechanical hindersfrom the blood flow with administration, either before or after, ofneuroprotective agents, may help saving ischemic neurons in the brainfrom irreversible injury, including apoptosis. However, as of today noneuroprotective agent has been provided for successful treatment ofstroke. It therefore appears that there still is a need for improvedtreatment of stroke, in particular improved treatment by administrationof neuroprotective agents, preferably in combination with the removal ofblood clots in the ischemic brain.

SUMMARY OF THE INVENTION

According to one aspect, compounds are provided that are Nox inhibitors,for use in therapy. More specifically, compounds that are Nox4inhibitors are provided for use in therapy. According to another aspect,compounds are provided that are effective in the treatment of diseasesassociated with, e.g. caused or driven by, elevated Nox activity, morespecifically elevated Nox4 activity.

According to a further aspect, compounds are provided that are Noxinhibitors, more specifically Nox4 inhibitors, for use in the treatmentof disorders, associated with elevated Nox activity, more specificallyelevated Nox4 activity.

Thus, according to the present invention, a compound is provided offormula (I)

each R¹, R² and R³ is independently selected from halogen, R⁵O(CH₂)_(q),R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl, alkynyl andcycloalkyl optionally being substituted with at least one halogen;each R⁴ is independently selected from halogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl; said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen;each R⁵ is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, and C3-C6 cycloalkyl; said alkyl, alkenyl, alkynyl andcycloalkyl optionally being substituted with at least one halogen;each R⁶ and R⁷ is independently selected from H, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl; said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen;X is NH, CH₂ or C(O);Y is NH; CH₂ or C(O);m is an integer of from 0 to 5;n is an integer of from 0 to 5;p is an integer of from 0 to 4; andq is an integer of from 0 to 3;or a pharmaceutically acceptable salt thereof,for use in the treatment of a condition or disorder associated with Nox,preferably Nox4.

Examples of such conditions and disorders e.g. are those mentionedherein above as related to or mediated by Nox, for example conditionsand disorders selected from cardiovascular disorders, endocrinedisorders, respiratory disorders, metabolism disorders, skin disorders,bone disorders, neuroinflammatory and/or neurodegenerative disorders,kidney diseases, reproduction disorders, endocrine disorders, diseasesaffecting the eye and/or the lens and/or conditions affecting the innerear, inflammatory disorders, liver diseases, pain, cancers, allergicdisorders, traumatisms, septic, hemorrhagic and anaphylactic shock,diseases or disorders of the gastrointestinal system, angiogenesis,angiogenesis-dependent conditions, as well as lung infections, acutelung injury, pulmonary arterial hypertension, obstructive lungdisorders, fibrotic lung disease, and lung cancer.

According to one aspect, there is provided a method of inhibiting theactivity of Nox, in particular Nox4, in a mammal in need thereof, byadministering to said mammal a compound of formula (I) as defined hereinabove.

According to one aspect, the compounds of the present invention are foruse as neuroprotective agents in the treatment of stroke, e.g. ischemicstroke.

According to one aspect, the use of a compound as defined herein isprovided, for the manufacturing of a medicament for the treatment of anyof the disorders mentioned herein.

According to one aspect, there is provided a compound selected from

-   N²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;

-   N²-(3-chloro-4-methylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;

-   6-((4-phenylpiperazin-1-yl)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine;

-   N²-phenyl-6-((4-phenylpiperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;

-   6-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-N²-phenyl-1,3,5-triazine-2,4-diamine;    or a pharmaceutically acceptable salt thereof, for use in therapy.

In another aspect, a pharmaceutical composition is provided, comprising

-   N²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;-   N²-(3-chloro-4-methylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;-   6-((4-phenylpiperazin-1-yl)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine;-   N²-phenyl-6-((4-phenylpiperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;    or-   6-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-N²-phenyl-1,3,5-triazine-2,4-diamine;    or a pharmaceutically acceptable salt thereof and optionally at    least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows dose-response curves for 4 different compounds of theinvention in Nox4-transfected TRex-293 cells, at 11 concentrationsobtained by serial dilution 1:3 of a 200 μM solution of tested compound:A)N²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine,B)N²-(3-chloro-4-methylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine,C)6-((4-phenylpiperazin-1-yl)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine,D)N²-phenyl-6-((4-phenylpiperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine,and E)6-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-N²-phenyl-1,3,5-triazine-2,4-diamine.

FIG. 2 is a bar chart showing the mean infarct volume, in mm³, in brainfrom stroke induced mice treated by i.p. injection ofN²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine(M4) or of vehicle (Control), respectively.

DETAILED DESCRIPTION OF THE INVENTION

In general any term used herein shall be given its normal meaning asaccepted within the field to which the present invention belongs. Forthe sake of clarity, however, some definitions will be given hereinbelow, and shall apply throughout the specification and the appendedclaims, unless otherwise specified or apparent from the context.

The term “endocrine disorder” refers to disorders of the endocrinesystem and may be as well endocrine gland hyposecretion ashypersecretion, or tumors of endocrine glands. Diabetes and polycysticovarian syndrome are examples of endocrine disorders.

The term “cardiovascular disorder or disease” comprises atherosclerosis,especially diseases or disorders associated with endothelial dysfunctionincluding but not limited to hypertension, cardiovascular complicationsof Type I or Type II diabetes, intimal hyperplasia, coronary heartdisease, cerebral, coronary or arterial vasospasm, endothelialdysfunction, heart failure including congestive heart failure,peripheral artery disease, restenosis, trauma caused by a stent, stroke,ischemic attack, vascular complications such as after organtransplantation, myocardial infarction, hypertension, formation ofatherosclerotic plaques, platelet aggregation, angina pectoris,aneurysm, aortic dissection, ischemic heart disease, cardiachypertrophy, pulmonary embolus, thrombotic events including deep veinthrombosis, injury caused after ischemia by restoration of blood flow oroxygen delivery as in organ transplantation, open heart surgery,angioplasty, hemorrhagic shock, angioplasty of ischemic organs includingheart, brain, liver, kidney, retina and bowel.

The term “respiratory disorder or disease” comprises bronchial asthma,bronchitis, allergic rhinitis, adult respiratory syndrome, cysticfibrosis, lung viral infection (influenza), pulmonary hypertension,idiopathic pulmonary fibrosis and chronic obstructive pulmonary diseases(COPD).

The term “allergic disorder” includes hay fever and asthma.

The term “traumatism” includes polytraumatism.

The term “disease or disorder affecting the metabolism” includesobesity, metabolic syndrome and Type II diabetes.

The term “skin disease” or disorder” includes psoriasis, eczema,dermatitis, wound healing and scar formation.

The term “bone disorder” includes osteoporosis, osteoporasis,osteosclerosis, periodontitis, and hyperparathyroidism.

The term “neurodegenerative disease or disorder” comprises a disease ora state characterized by a central nervous system (CNS) degeneration oralteration, especially at the level of the neurons such as Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, epilepsy and muscular dystrophy. It further comprisesneuro-inflammatory and demyelinating states or diseases such asleukoencephalopathies, and leukodystrophies.

The term “demyelinating” is referring to a state or a disease of the CNScomprising the degradation of the myelin around the axons. In thecontext of the invention, the term demyelinating disease is intended tocomprise conditions which comprise a process that demyelinate cells suchas multiple sclerosis, progressive multifocal leukoencephalopathy (PML),myelopathies, any neuroinflammatory condition involving autoreactiveleukocyte within the CNS, congenital metabolic disorder, a neuropathywith abnormal myelination, drug induced demyelination, radiation induceddemyelination, a hereditary demyelinating condition, a prion induceddemyelinating condition, encephalitis induced demyelination or a spinalcord injury. Preferably, the condition is multiple sclerosis.

The term “kidney disease or disorder” includes diabetic nephropathy,renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides andplatinum compounds and hyperactive bladder. In a particular embodiment,the term according to the invention includes chronic kidney diseases ordisorders.

The term “reproduction disorder or disease” includes erectiledysfunction, fertility disorders, prostatic hypertrophy and benignprostatic hypertrophy.

The term “disease or disorder affecting the eye and/or the lens”includes cataract including diabetic cataract, re-opacification of thelens post cataract surgery, diabetic and other forms of retinopathy.

The term “conditions affecting the inner ear” includes presbyacusis,tinnitus, Meniere's disease and other balance problems,utriculolithiasis, vestibular migraine, and noise induced hearing lossand drug induced hearing loss (ototoxicity).

The term “inflammatory disorder or disease” means inflammatory boweldisease, sepsis, septic shock, adult respiratory distress syndrome,pancreatitis, shock induced by trauma, bronchial asthma, allergicrhinitis, rheumatoid arthritis, chronic rheumatoid arthritis,arteriosclerosis, intracerebral hemorrhage, cerebral infarction, heartfailure, myocardial infarction, psoriasis, cystic fibrosis, stroke,acute bronchitis, chronic bronchitis, acute bronchiolitis, chronicbronchiolitis, osteoarthritis, gout, myelitis, ankylosing spondylitis,Reuter syndrome, psoriatic arthritis, spondylarthritis, juvenilearthritis or juvenile ankylosing spondylitis, reactive arthritis,infectious arthritis or arthritis after infection, gonococcal arthritis,syphilitic arthritis, Lyme disease, arthritis induced by “angiitissyndrome,” polyarteritis nodosa, anaphylactic angiitis, Luegenecgranulomatosis, rheumatoid polymyalgia, articular cell rheumatism,calcium crystal deposition arthritis, pseudogout, non-arthriticrheumatism, bursitis, tendosynovitis, epicondyle inflammation (tenniselbow), carpal tunnel syndrome, disorders by repetitive use (typing),mixed form of arthritis, neuropathic arthropathy, hemorrhagic arthritis,vascular peliosis, hypertrophic osteoarthropathy, multicentricreticulohistiocytosis, arthritis induced by specific diseases, bloodpigmentation, sickle cell disease and other hemoglobin abnormality,hyperlipoproteinemia, dysgammaglobulinemia, hyperparathyroidism,acromegaly, familial Mediterranean fever, Bechet's disease, systemicautoimmune disease erythematosus, multiple sclerosis and Crohn's diseaseor diseases like relapsing polychondritis, chronic inflammatory boweldiseases (IBD) or the related diseases which require the administrationto a mammal in a therapeutic effective dose of a compound expressed byFormula (I) in a sufficient dose to inhibit NADPH oxidase.

The term “liver diseases or disorders” include liver fibrosis, alcoholinduced fibrosis, steatosis and non-alcoholic steatohepatitis.

The term “arthritis” means acute rheumatic arthritis, chronic rheumatoidarthritis, chlamydial arthritis, chronic absorptive arthritis, anchylousarthritis, arthritis based on bowel disease, filarial arthritis,gonorrheal arthritis, gouty arthritis, hemophilic arthritis,hypertrophic arthritis, juvenile chronic arthritis, Lyme arthritis,neonatal foal arthritis, nodular arthritis, ochronotic arthritis,psoriatic arthritis or suppurative arthritis, or the related diseaseswhich require the administration to a mammal in a therapeutic effectivedose of a compound expressed by Formula (I) in a sufficient dose toinhibit NADPH oxidase.

The term “pain” includes hyperalgesia associated with inflammatory pain.

The term “cancer” means carcinoma (e.g., fibrosarcoma, myxosarcoma,liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma,periosteoma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, renal cancer, prostatic carcinoma, squamous cellcarcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatocellular carcinoma,cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma,Wilms' tumor, cervical cancer, orchioncus, lung cancer, small-cell lungcancer, lung adenocarcinoma, bladder cancer or epithelial cancer) or therelated diseases which require the administration to a mammal in atherapeutic effective dose of a compound expressed by the Formula (I) ina sufficient dose to inhibit NADPH oxidase.

The term “disease or disorders of the gastrointestinal system”, includesgastric mucosa disorders ischemic bowel disease management,enteritis/colitis, cancer chemotherapy, or neutropenia.

The term “angiogenesis” includes sprouting angiogenesis, intussusceptiveangiogenesis, vasculogenesis, arteriogenesis and lymphangiogenesis.Angiogenesis is the formation of new blood vessels from pre-existingcapillaries or post-capillary venules and occurs in pathologicalconditions such as cancers, arthritis and inflammation. A large varietyof tissues, or organs comprised of organized tissues, can supportangiogenesis in disease conditions including skin, muscle, gut,connective tissue, joints, bones and the like tissue in which bloodvessels can invade upon angiogenic stimuli. As used herein, the term“angiogenesis-dependent condition” is intended to mean a condition wherethe process of angiogenesis or vasculogenesis sustains or augments apathological condition. Vasculogenesis results from the formation of newblood vessels arising from angioblasts which are endothelial cellprecursors. Both processes result in new blood vessel formation and areincluded in the meaning of the term angiogenesis-dependent conditions.Similarly, the term “angiogenesis” as used herein is intended to includede novo formation of vessels such as those arising from vasculogenesisas well as those arising from branching and sprouting of existingvessels, capillaries and venules.

The term “angiogenesis inhibitory,” means which is effective in thedecrease in the extent, amount, or rate of neovascularization. Effectinga decrease in the extent, amount, or rate of endothelial cellproliferation or migration in the tissue is a specific example ofinhibiting angiogenesis. Angiogenesis inhibitory activity isparticularly useful in the treatment of any cancers as it targets tumorgrowth process and in the absence of neovascularization of tumor tissue,the tumor tissue does not obtain the required nutrients, slows ingrowth, ceases additional growth, regresses and ultimately becomesnecrotic resulting in killing of the tumor. Further, an angiogenesisinhibitory activity is particularly useful in the treatment of anycancers as it is particularly effective against the formation ofmetastases because their formation also requires vascularization of aprimary tumor so that the metastatic cancer cells can exit the primarytumor and their establishment in a secondary site requiresneovascularization to support growth of the metastases.

As used herein, “treatment” and “treating” and the like generally meanobtaining a desired pharmacological and physiological effect. The effectmay be prophylactic in terms of preventing or partially preventing adisease, symptom or condition thereof and/or may be therapeutic in termsof a partial or complete cure of a disease, condition, symptom oradverse effect attributed to the disease. The term “treatment” as usedherein covers any treatment of a disease in a mammal, particularly ahuman, and includes: (a) preventing the disease from occurring in asubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (b) inhibiting the disease, i.e., arresting itsdevelopment; or relieving the disease, i.e., causing regression of thedisease and/or its symptoms or conditions.

The term “subject” as used herein refers to mammals. For examples,mammals contemplated by the present invention include human, primates,domesticated animals such as cattle, sheep, pigs, horses and the like.

“An effective amount” refers to an amount of a compound that confers atherapeutic effect on the treated subject. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect).

The term “inhibitor” used in the context of the invention is defined asa molecule that inhibits completely or partially the activity of Nox, inparticular Nox4, and/or inhibits or reduces the generation of reactiveoxygen species (ROS).

“Pharmaceutically acceptable” means being useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes being useful forveterinary use as well as human pharmaceutical use.

The term Cn, where n is an integer, specifies that a radical or moietycontains n carbon atoms. The term Cn−Cm, where m and n are bothintegers, and m>n, refers to a radical or moiety containing n, n+1, n+2,. . . or m carbon atoms. Thus, the term C1-C6 alkyl refers to an alkylradical that may contain 1, 2, 3, 4, 5 or 6 carbon atoms. The term C0alkyl refers to a covalent bond.

An alkyl moiety according to the invention may be branched or linear,e.g. selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl,n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl.

A C1-C6 alkyl according to the invention more particularly may beselected from C1-05 alkyl, e.g. from C1-C4 alkyl, from C1-C3 alkyl, fromC1-C2 alkyl, or may be methyl.

The term “C2-C6 alkenyl” refers to a straight or branched chain alkenylhaving from 2 to 6 carbon atoms in the chain and that may have anyavailable number of double bonds in any available positions. Theconfiguration of the double bond may be (E) or (Z). Examples are vinyl,allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. A C2-C6 alkenylaccording to the invention, more specifically may be a C2-C4 alkenyl, ora C2-C3 alkenyl.

The term “C2-C6 alkynyl” refers to a straight or branched chain alkynylhaving from 2 to 6 carbon atoms in the chain and that may have anyavailable number of triple bonds in any available positions. Examplesare ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 2-pentene-4-ynyl. AC2-C6 alkynyl according to the invention, more specifically may be aC2-C4 alkynyl, or a C2-C3 alkynyl.

The term “C3-C6 cycloalkyl” refers to a cyclic alkyl radical having from3 to 6 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl.

By “substituted with at least one halogen” is meant that at least onehydrogen is replaced by a halogen, e.g. F. An example of an alkylsubstituted with at least one halogen is trifluoromethyl.

As used herein, and unless otherwise specified, the term “halogen” (or“halo”) means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).Any halogen according to the invention more particularly may be selectedfrom F and Cl.

In a compound of formula (I) as provided herein, each R¹, R² and R³ isindependently selected from halogen, R⁵O(CH₂)_(q), R⁵S(CH₂)_(q),R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,and C3-C6 cycloalkyl, said alkyl, alkenyl, alkynyl and cycloalkyloptionally being substituted with at least one halogen.

In some embodiments, each R¹, R² and R³ is independently selected fromhalogen, R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), and C1-C6 alkyl,said alkyl, optionally being substituted with at least one halogen.

In some other embodiments, each R¹, R² and R³ is independently selectedfrom halogen, R⁵O(CH₂)_(q), R⁶R⁷N(CH₂)_(q), and C1-C6 alkyl, said alkyl,optionally being substituted with at least one halogen.

As noted herein above, each R¹ is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen.

In some embodiments, each R¹ is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl, alkynyl andcycloalkyl optionally being substituted with at least one halogen.

In some other embodiments, each R¹ is independently selected fromhalogen, R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl, alkynyl andcycloalkyl optionally being substituted with at least one halogen.

In still other embodiments, each R¹ is independently selected fromhalogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6cycloalkyl, said alkyl, alkenyl, alkynyl and cycloalkyl optionally beingsubstituted with at least one halogen.

In some particular embodiments, each R¹ is independently selected fromhalogen and C1-C6 alkyl, said alkyl optionally being substituted with atleast one halogen.

In some embodiments, each R¹ is independently selected from C1-C6 alkyl,said alkyl optionally being substituted with at least one halogen.

In some embodiments, each R¹ is independently selected from halogen.

In any of the above embodiments, when R¹ is halogen, it especially maybe selected from F and Cl, and in particular R¹ may be Cl.

As noted herein above, each R² is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen.

In some embodiments, each R² is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl, C2-C6 alkenyl,C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl, alkynyl andcycloalkyl optionally being substituted with at least one halogen.

In some other embodiments, each R² is independently selected fromhalogen, R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl, alkynyl andcycloalkyl optionally being substituted with at least one halogen.

In still other embodiments, each R² is independently selected fromhalogen, R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), and C1-C6 alkyl, said alkyloptionally being substituted with at least one halogen.

In further embodiments, each R² is independently selected from halogen,R⁵O(CH₂)_(q), and R⁵S(CH₂)_(q).

In some embodiments, each R² is independently selected fromR⁵O(CH₂)_(q), and R⁵S(CH₂)_(q).

In some other embodiments, each R² is independently selected fromhalogen, and R⁵O(CH₂)_(q).

In some embodiments, each R² is independently selected fromR⁵O(CH₂)_(q).

In some other embodiments, each R² is independently selected fromhalogen.

As noted herein above, R³ is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen.

In some embodiments, R³ is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl,said alkyl optionally being substituted with at least one halogen.

In some other embodiments, R³ is R⁶R⁷N(CH₂)_(q).

In a compound of formula (I), each R⁴ is independently selected fromhalogen, e.g. F, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6cycloalkyl; said alkyl, alkenyl, alkynyl and cycloalkyl optionally beingsubstituted with at least one halogen.

In some embodiments, each R⁴ is independently selected from halogen,e.g. F and C1-C6 alkyl, said alkyl, optionally being substituted with atleast one halogen.

In a compound of formula (I), any R⁵, when present, is independentlyselected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6cycloalkyl; said alkyl, alkenyl, alkynyl and cycloalkyl optionally beingsubstituted with at least one halogen.

In some embodiments, any R⁵, when present, is independently selectedfrom C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl;said alkyl, alkenyl, alkynyl and cycloalkyl optionally being substitutedwith at least one halogen.

In some embodiments, any R⁵, when present, is independently selectedfrom H and C1-C6 alkyl, said alkyl optionally being substituted with atleast one halogen.

In some embodiments, any R⁵, when present, is independently selectedfrom C1-C6 alkyl, said alkyl optionally being substituted with at leastone halogen.

In a compound of formula (I), each R⁶ and R⁷ is independently selectedfrom H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl;said alkyl, alkenyl, alkynyl and cycloalkyl optionally being substitutedwith at least one halogen.

In some embodiments, each R⁶ and R⁷ is independently selected from H andC1-C6 alkyl, said alkyl optionally being substituted with at least onehalogen.

In some embodiments, R⁶ is as defined herein above and R⁷ is H. In otherembodiments, both R⁶ and R⁷ are H.

In a compound of formula (I) as defined herein, X is NH, CH₂ or C(O). Insome embodiments, X is NH or CH₂. In other embodiments, X is NH.

In a compound of formula (I) as defined herein, Y is NH, CH₂ or C(O). Insome embodiments, Y is NH or CH₂. In other embodiments, Y is CH₂.

The integer m, representing the number of moieties R¹ in a compound offormula (I), ranges from 0 to 5, from 0 to 4, from 0 to 3, or from 0 to2. In some embodiments, m is at least 1, e.g. m is 1-5, 1-4, or 1-3. Insome embodiments, m is 1 or 2, e.g. m is 2.

In some embodiments, when m is an integer of 1 or higher, one R¹ isattached to the phenyl ring in para position or in meta position. Inother words, the phenyl ring is substituted on any of carbon atomsnumber 3, 4 or 5 of the phenyl ring, assuming that the X link to thetriazine ring is attached at carbon atom number 1 of the phenyl ring.

In some embodiments, when m is an integer of 1 or higher, one R¹ isattached to the phenyl ring in para position.

In some embodiments, when m is an integer of 2 or higher, one R¹ isattached to the phenyl ring in para position and one R¹ is attached inmeta position.

The integer n, representing the number of moieties R² in a compound offormula (I), ranges from 0 to 5, from 0 to 4, from 0 to 3, or from 0 to2. In some embodiments, n is at least 1, e.g. n is 1-5, 1-4, or 1-3. Insome embodiments, n is 1 or 2, e.g. n is 1. In some embodiments, n is 0or 1.

In some embodiments, when n is an integer of 1 or higher, one R² isattached to the phenyl ring in para position or in meta position. Inother words, the phenyl ring is substituted on any of carbon atomsnumber 3, 4 or 5 of the phenyl ring, assuming that the Y link to thetriazine ring is attached at carbon atom number 1 of the phenyl ring.

In some embodiments, when n is an integer of 1 or higher, e.g. n is 1,one R² is attached to the phenyl ring in meta position, e.g. R² isR⁵O(CH₂)_(q) in meta position. For example, n is 1 and R² is in metaposition and is R⁵O(CH₂)_(q).

In some embodiments, when n is an integer of 1 or higher, e.g. n is 1,one R² is attached to the phenyl ring in para position, e.g. R² is ahalogen, such as F, in para position.

The integer p, representing the number of moieties R⁴ in a compound offormula (I), ranges from 0 to 4, from 0 to 3, or from 0 to 2, e.g. p is0 or 1. In some embodiments, p is 0.

The integer q in any moiety R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q),and CN(CH₂)_(q) is selected from 0, 1, 2 and 3. In some embodiments, anyq is selected from 0, 1 and 2; or from 0 and 1. In some embodiments, qis 0, i.e. any moiety R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), orCN(CH₂)_(q) is R⁵O—, R⁵S—, R⁶R⁷N—, or CN—.

In some particular embodiments, X is NH and Y is CH₂. In some otherparticular embodiments, X is NH, Y is CH₂, and p is 0. In still otherparticular embodiments, X is NH, Y is CH₂, p is 0, and R³ is R⁶R⁷N.

Many further embodiments are possible and contemplated within the scopeof formula (I), some of which are illustrated in a non-limiting fashionin the following Table 1.

TABLE 1 Exemplary embodiments of a compound of formula (I) according tothe invention Special feature(s) of embodiment Strucural formula ofembodiment (a) X is NH

(Ia) (b) Y is CH₂

(Ib) (C) R³ is NR⁶R⁷(CH₂)q

(Ic) (d) p is 0

(Id) (e) m is at least 1, and one R¹ is in para position

(Ie) (f) n is at least 1, and one R² is in meta position

(If) (g) R³ is NR⁶R⁷(CH₂)q, and q is 0

(Ig) (h) = (a) + (b)

(Ih) (i) = (h) + (c)

(Ii) (j) = (i) + (d)

(Ij) (k) = (h) + (g)

(Ik) (m) = (k) + (d)

(Im) (n) = (m) wherein R⁶ and R⁷ are both H

(In)

In Table 1 the sum of e.g. (a) and (b), written as (h)=(a)+(b), refersto an embodiment (“embodiment (h)”) comprising the features ofembodiments (a) and (b), respectively, i.e. wherein X has been specifiedas NH, and Y has been specified as CH₂, and so on with otherembodiments.

Unless apparent from the context or specified herein, any reference to acompound of formula (I) also is intended as applying to a compound anyone of the formulas (Ia) to (In), as illustrated in Table 1. It shouldhowever be realized that many other embodiments are also possible withinthe scope of the invention.

In some particular embodiments, the compound of the invention isselected from

-   N²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;-   N²-(3-chloro-4-methylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;-   6-((4-phenylpiperazin-1-yl)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine;-   N²-phenyl-6-((4-phenylpiperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;    and-   6-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-N²-phenyl-1,3,5-triazine-2,4-diamine;    or from pharmaceutically acceptable salts thereof.

The compounds of formula (I) can be prepared by methods well known inthe art, from readily available starting materials using general methodsand procedures. Some compounds of formula (I) may be commerciallyavailable, e.g. from Vitas laboratories, Moscow, 125252, Russia.

The compounds of the present invention are Nox inhibitors. Morespecifically, the compounds of the present invention are Nox4inhibitors. The capacity of inhibiting predominantly one particular Noxiso form, i.e. Nox4, is considered to be an important advantage of thepresent compounds, in view of the fact that Nox isoforms not only areinvolved in diseases, as Nox4, but also have various importantbiological functions in the living body.

Depending on the process conditions the end products of formula (I) areobtained either in neutral or salt form. Both the free base and the freeacid, as well as the salts of these end products are within the scope ofthe invention. Acid addition salts of the inventive compounds may in amanner known per se be transformed into the free base using basic agentssuch as alkali or by ion exchange. The free base obtained may also formsalts with organic or inorganic acids. Alkali addition salts of theinventive compounds may in a manner known per se be transformed into thefree acid by using acidic agents such as acid or by ion exchange. Thefree acid obtained may also form salts with organic or inorganic bases.

In the preparation of acid or base addition salts, preferably such acidsor bases are used which form suitably therapeutically acceptable salts.Examples of such acids are hydrohalogen acids, sulfuric acid, phosphoricacid, nitric acid, aliphatic, alicyclic, aromatic or heterocycliccarboxylic or sulfonic acids, such as formic acid, acetic acid,propionic acid, succinic acid, glycolic acid, lactic acid, malic acid,tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleicacid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonicacid, ethanesulfonic acid, hydroxyethanesulfonic acid,halogenbenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonicacid. Base addition salts include those derived from inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like, and organic bases such asalkoxides, alkyl amides, alkyl and aryl amines, and the like. Examplesof bases useful in preparing salts of the present invention includesodium hydroxide, potassium hydroxide, ammonium hydroxide, potassiumcarbonate, and the like.

There may be several stereoisomers of the compounds of the invention,including enantiomers and diastereomers. Enantiomers can be present intheir pure forms, or as racemic (equal) or unequal mixtures of twoenantiomers. Diastereomers can be present in their pure forms, or asmixtures of diastereomers. Diastereomers also include geometric isomers,which can be present in their pure cis or trans forms or as mixtures ofthose.

Pharmaceutical formulations are usually prepared by mixing the activesubstance, i.e. a compound of the invention, or a pharmaceuticallyacceptable salt thereof, with conventional pharmaceutical excipients.The formulations can be further prepared by known methods such asgranulation, compression, microencapsulation, spray coating, etc. Theformulations may be prepared by conventional methods in the dosage formof tablets, capsules, granules, powders, syrups, suspensions,suppositories or injections. Liquid formulations may be prepared bydissolving or suspending the active substance in water or other suitablevehicles. Tablets and granules may be coated in a conventional manner.

For clinical use, the compounds of the invention are formulated intopharmaceutical formulations for oral, rectal, parenteral or other modeof administration. These pharmaceutical preparations are a furtherobject of the invention.

Usually the effective amount of active compounds is between 0.1-95% byweight of the preparation, preferably between 0.2-20% by weight inpreparations for parenteral use and preferably between 1 and 50% byweight in preparations for oral administration.

The dose level and frequency of dosage of the specific compound willvary depending on a variety of factors including the potency of thespecific compound employed, the metabolic stability and length of actionof that compound, the patient's age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the condition to be treated, and thepatient undergoing therapy. The daily dosage may, for example, rangefrom about 0.001 mg to about 100 mg per kilo of body weight,administered singly or multiply in doses, e.g. from about 0.01 mg toabout 25 mg each. Normally, such a dosage is given orally but parenteraladministration may also be chosen.

In the preparation of pharmaceutical formulations containing a compoundof the present invention in the form of dosage units for oraladministration the compound selected may be mixed with solid, powderedingredients, such as lactose, saccharose, sorbitol, mannitol, starch,amylopectin, cellulose derivatives, gelatin, or another suitableingredient, as well as with disintegrating agents and lubricating agentssuch as magnesium stearate, calcium stearate, sodium stearyl fumarateand polyethylene glycol waxes. The mixture is then processed intogranules or pressed into tablets.

Soft gelatine capsules may be prepared with capsules containing amixture of the active compound or compounds of the invention, vegetableoil, fat, or other suitable vehicle for soft gelatine capsules. Hardgelatine capsules may contain granules of the active compound. Hardgelatine capsules may also contain the active compound in combinationwith solid powdered ingredients such as lactose, saccharose, sorbitol,mannitol, potato starch, corn starch, amylopectin, cellulose derivativesor gelatine.

Dosage units for rectal administration may be prepared (i) in the formof suppositories which contain the active substance mixed with a neutralfat base; (ii) in the form of a gelatine rectal capsule which containsthe active substance in a mixture with a vegetable oil, paraffin oil orother suitable vehicle for gelatine rectal capsules; (iii) in the formof a ready-made micro enema; or (iv) in the form of a dry micro enemaformulation to be reconstituted in a suitable solvent just prior toadministration.

Liquid preparations for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions containing from0.2% to 20% by weight of the active ingredient and the remainderconsisting of sugar or sugar alcohols and a mixture of ethanol, water,glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain colouring agents, flavouring agents,saccharine and carboxymethyl cellulose or other thickening agent. Liquidpreparations for oral administration may also be prepared in the form ofa dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral, e.g. intravenous, administration may beprepared as a solution of a compound of the invention in apharmaceutically acceptable solvent, preferably in a concentration from0.1% to 10% by weight. These solutions may also contain stabilizingingredients and/or buffering ingredients and are dispensed into unitdoses in the form of ampoules or vials. Solutions for parenteraladministration may also be prepared as a dry preparation to bereconstituted with a suitable solvent extemporaneously before use. Thecompounds of the present invention may also be used or administered incombination with one or more additional therapeutically active agents.The components may be in the same formulation or in separateformulations for administration simultaneously or sequentially.

Accordingly, in a further aspect of the invention, there is provided acombination product comprising:

(A) a compound of the invention, as defined herein; and

(B) another therapeutic agent; whereby (A) and (B) is formulated inadmixture with a pharmaceutically acceptable excipient.

Such combination products provide for the administration of a compoundof the invention in conjunction with the other therapeutic agent, andmay thus be presented either as separate formulations, wherein at leastone of those formulations comprises a compound of the invention, and atleast one comprises the other therapeutic agent, or may be presented(i.e. formulated) as a combined preparation (i.e. presented as a singleformulation including a compound of the invention and the othertherapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention,as hereinbefore defined, another therapeutic agent, and apharmaceutically acceptable excipient, e.g. an adjuvant, diluent orcarrier; or

(2) a kit of parts comprising, as components:

(a) a pharmaceutical formulation including a compound of the invention,as defined herein, in admixture with a pharmaceutically acceptableexcipient, e.g. an adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including another therapeutic agent inadmixture with a pharmaceutically acceptable excipient, e.g. anadjuvant, diluent or carrier, which components (a) and (b) are eachprovided in a form that is suitable for administration in conjunctionwith the other.

In some particular embodiments, the compound of the invention is used ina combination with an antitumor agent in the treatment of a malignanthyperproliferative disease. Such combination therapy may be particularlyuseful in cancer chemotherapy, to counteract an anti-apoptotic effect ofNox4 that may lead to tumor resistance to the antitumor agent.

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention,as hereinbefore defined, an antitumor agent, and a pharmaceuticallyacceptable excipient, e.g. an adjuvant, diluent or carrier; or

(2) a kit of parts comprising, as components:

(a) a pharmaceutical formulation including a compound of the invention,as defined herein, in admixture with a pharmaceutically acceptableexcipient, e.g. an adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including an antitumor agent inadmixture with a pharmaceutically acceptable excipient, e.g. anadjuvant, diluent or carrier, which components (a) and (b) are eachprovided in a form that is suitable for administration in conjunctionwith the other.

The components (a) and (b) in any of the above kit of parts may beadministered at the same time, in sequence, or separately from eachother.

The compounds of the present invention may also be used or administeredin combination with other modes of treatment such as irradiation for thetreatment of cancer.

According to one aspect, there is provided a method of inhibiting theactivity of Nox, in particular Nox4, in a patient in need thereof, byadministering to said patient a therapeutically effective amount of acompound of formula (I) as defined herein. The patient may be anymammal, but preferably is a human.

The patient to be treated may be one suffering from a condition ordisorder associated with an elevated activity of Nox, in particularNox4, or a patient at risk of developing such a condition or disorder.Examples of such conditions and disorders are cardiovascular disorders,respiratory disorders, metabolism disorders, skin disorders, bonedisorders, neuroinflammatory and/or neurodegenerative disorders, kidneydiseases, reproduction disorders, diseases affecting the eye and/or thelens and/or conditions affecting the inner ear, inflammatory disorders,liver diseases, pain, cancers, allergic disorders, traumatisms, septic,hemorrhagic and anaphylactic shock, diseases or disorders of thegastrointestinal system, angiogenesis, angiogenesis-dependentconditions, lung infections, acute lung injury, pulmonary arterialhypertension, obstructive lung disorders, fibrotic lung disease, andlung cancer.

In one embodiment, the compounds of the present invention are for use inthe treatment of stroke. In one particular embodiment, the stroke isischemic. The compounds of the present invention are considered to haveneuroprotective activity in the treatment of stroke. Therefore, thecompounds of the present invention suitable are used in combination withremoval of blood clots in the treatment of ischemic stroke. In oneparticular embodiment, the compounds of the present invention are usedin combination with tPA in the treatment of ischemic stroke.

The invention will be illustrated by the following, non-limitingExamples.

EXAMPLES Example 1 Cell-Based Assays and Analytical Chemistry

1. Cell Viability

1.1 Celltiter-Blue Cell Viability Assay (Promega)

The assay is based on the ability of the cells to reduce resazurin toresorufin as a measure of viability. TREx™-293 Nox4 cells were culturedin a T-225 flask, collected by trypsination and re-suspended in cellmedium. 20,000 cells in 90 μl were seeded to 96-well cell culture plates(black with transparent bottom). One background plate with 90 μl cellmedium only was also prepared.

After 24 hours, 10 μl of compound, diluted to 10 times finalconcentration in 37° C. cell medium, were added to cell and backgroundplates. The compounds were tested in duplicate at a final concentrationof 10 μM. Chlorpromazine, at a final concentration of 100 μM, was addedas positive control. After 24 hours of treatment, 20 μl ofCellTiter-Blue reagent were added and the plate was incubated for 120min at 37° C. Resorufin fluorescence was read in Victor2V plate reader.All experimental values were corrected for background before analysis ofthe cell viability.

1.2 CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega)

The assay is based on lactate dehydrogenase (LDH) activity insurrounding cell medium as a measure of membrane integrity. Membraneintegrity can be affected by apoptosis, necrosis or chemicals. TREx™-293Nox4 cells were cultured in a T-225 flask, collected by trypsination andre-suspended in HBSS to 100,000 cells per ml. 90 μl of cell suspensionwere added to each well of a V-bottom polypropylene 96-well plate. Onebackground plate was prepared with HBSS only. Compounds were diluted inHBSS to 10 times final concentration and 10 μl was added per well. Thecompounds were tested in duplicate at a final concentration of 10 μM.

Plates were incubated 3 hours at 37° C. 45 minutes before end ofincubation time, 10 μl of lysis solution (Triton X-100) were added tototal control wells to estimate total LDH content of cells. SpontaneousLDH leakage was determined with un-treated cells.

Cell plates were centrifuged 250×g for 5 minutes and 50 μl ofsupernatant were transferred to 96-well Spectraplates. 50 μl ofreconstituted substrate mix were added and plates were incubated for 30minutes at room temperature. 50 μl of stop solution were added andplates were read in SpectraMax® at a wavelength of 490 nm. Compoundspecific background was subtracted and % cytotoxcity was calculated as:[(Experimental−Spontaneous)/(Total−Spontaneous)]*100%.

When tested in the two cell viability assays, none of the inventivecompounds showed any significant cell toxicity effects.

2. Dose-Response Curves

Dose-response measurements with the Amplex® Red based assay wereperformed as follows: Compound serial dilution was carried out using thesystem based on the liquid handler Janus® (Perkin Elmer) and schedulingsoftware Overlord (Process Analysis and Automation).

Starting with compound plates with 15 μl 10 mM compound stock solutionin DMSO, 10 μl of DMSO were added to columns of compound plate(Flexdrop). Serial dilution was performed by adding 5 μl compoundsolution to 10 μl DMSO (1:3) to 11 concentrations. To each well of thecompound plate 90 μl of assay buffer were added. After mixing, 10 μlwere transferred from each well of the compound plate to wells of anassay plate, followed by addition of 20 μl detection mix and 20 μl of asuspension of TREx™-293 Nox4 cells. The assay plate then was incubatedfor 40-60 min at room temperature.

Data was analyzed using a custom calculation template in Activitybase XE(IDBS). Raw fluorescence data was transformed to % inhibition using thebuilt-in formula:

${\%\mspace{14mu}{inhibition}} = {100 - {\frac{{RawData}_{Compound} - {RawData}_{Low}}{{RawData}_{High} - {RawData}_{Low}} \times 100}}$

Dose-response curves were fitted using non-linear regression with fourparameter logistic formula. FIGS. 1A-E show dose-response curves forsome compounds of the invention. The tested compounds have 1050 valuesranging from about 1 μM to about 68 μM.

Example 2 In Vivo Study: Stroke Animal Model

Mice (10-12 wk), wild type C57BI6, 6 animals, were used:

Control (n=3) stroke induced mouse treated i.p. with vehicle 2 h and 12h.

Test (n=3) stroke induced mouse treated i.p. with inventive compound M4(N²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine).

M4 preparation for intra peritoneal i.p. administration: 3.5 mg of M4were first dissolved in 1 ml of DMSO. After the substance was totallydissolved, 5 ml of 20% Cremophor ELP in PBS (phosphate buffered salinesolution) was added. Thereafter an additional 4 ml of PBS was added. The20% Cremophor ELP solution was prepared by dissolving 10.5 g ofCremophor in 50 ml of PBS.

Final concentration of the injection solution: 0.35 mg/ml.

Injection volume of M4: The dose was 3.2 mg/kg, calculated for eachanimal at each event of administration (2 h and 12 h).

Procedure:

-   -   1. Transient middle cerebral artery occlusion (tMCAO) by        blocking with a filament for 1 h.    -   2. Reperfusion after 1 h by removing filament    -   3. Injection of M4 by i.p. after 2 h and repeated injection i.p.        after 12 h    -   4. Sacrifice the animal after 24 h and infarct size is        determined by triphenyl tetrazolium chloride (TTC) staining—Thus        the procedure of middle cerebral artery occlusion (MCAO); 1 h        occlusion and 23 h reperfusion.    -   5. Stroke analysis was performed as described previously        (Experimental Neurology 200 (2006), pp. 480-485; Circulation May        1, 2007, pp. 2323-2330). To determine infarct size, mice were        killed 24 h after tMCAO, pMCAO, or cortical photothrombosis.        Brains were cut in 2-mm-thick coronal sections using a mouse        brain slice matrix (Harvard Apparatus). The slices were stained        with 2% TTC (Sigma-Aldrich) to visualize the infarcts.        Planimetric measurements (ImageJ software, United States        National Institutes of Health), calculating lesion volumes, were        corrected for brain edema as described previously (Ann Neurol        2003; 54:330-342).        Animal Studies

Animal studies were approved by the Regierung von Unterfranken andconducted according to the recently published recommendations forresearch in mechanism-driven basic stroke studies. Adult male C57/BL6mice (20 to 25 g) were purchased from Charles River (Sulzfeld, Germany).The tMCAO model was used to induce focal cerebral ischemia as describedin detail elsewhere. Briefly, mice were anesthetized with 2% isofluranein a 70% N2O/30% O2 mixture. A servo-controlled heating blanket was usedto maintain core body temperature close to 37° C. throughout surgery.After a midline neck incision was made, a standardized siliconrubber-coated 6.0 nylon monofilament (60-1720RE, Doccol, Redlands,Calif.) was inserted into the right common carotid artery and advancedvia the internal carotid artery to occlude the origin of the MCA. After1 hour, mice were reanesthetized, and the occluding filament was removedto allow reperfusion. All animals were operated on by the same operatorto reduce infarct variability; operation time per animal did not exceed15 minutes.

Determination of Infarct Size

Mice were killed 24 hours after tMCAO. Brains were quickly removed andcut into 2-mm-thick coronal sections using a mouse brain slice matrix.The slices were stained with 2% 2,3,5-triphenyltetrazolium chloride(TTC; Sigma-Aldrich, Seelze, Germany) in PBS to visualize theinfarctions. Planimetric measurements (ImageJ software, NationalInstitutes of Health, Bethesda, Md.) were performed by researchersblinded to the treatment group and were used to calculate lesionvolumes, which were corrected for brain edema as described elsewhere.The occurrence of Intra Cerebral Hemorrhage (ICH) was macroscopicallyassessed on whole brains and again after the 2-mm-thick coronal brainslices were cut (see above) before TTC staining. Brains showing ICH wereexcluded from the assessment of infarct volume. The results for the treemice treated with M4 and the three control mice, respectively, are shownin Table 2. FIG. 2 is a bar chart showing the mean infarct volume forthe group treated with M4 and the control group, respectively.

TABLE 2 Infarct volume, mm³ Animals treated with M4 Control animals 73107 145 224 134 204

The invention claimed is:
 1. A method of inhibiting NOX4 in a mammal,wherein the inhibition of NOX4 is used to treat a disorder or conditionselected from the group consisting of endocrine disorders,cardiovascular disorders, respiratory disorders, metabolism disorders,skin disorders, bone disorders, neuroinflammatory and/orneurodegenerative disorders, kidney diseases, reproduction disorders,diseases affecting the eye and/or the lens and/or conditions affectingthe inner ear, inflammatory disorders, liver diseases, pain, cancers,lung cancer, allergic disorders, traumatisms, septic, hemorrhagic andanaphylactic shock, diseases or disorders of the gastrointestinalsystem, angiogenesis, angiogenesis-dependent conditions, lunginfections, acute lung injury, pulmonary arterial hypertension,obstructive lung disorders, and fibrotic lung disease, the methodcomprising administering, to a mammal in need thereof, a compound offormula (I)

wherein each R¹, R² and R³ is independently selected from halogen,R⁵O(CH₂)_(q), R⁵S(CH₂)_(q), R⁶R⁷N(CH₂)_(q), CN(CH₂)_(q), C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen; each R⁴ is independently selected from halogen, C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen; each R⁵ is independently selected from H, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen; each R⁶ and R⁷ is independently selected from H, C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen; X is NH, CH₂ or C(O); Y is NH; CH₂ or C(O); m is an integer offrom 0 to 5; n is an integer of from 0 to 5; p is an integer of from 0to 4; and q is an integer of from 0 to 3; or a pharmaceuticallyacceptable salt thereof.
 2. The method according to claim 1, whereineach R¹ is independently selected from halogen, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl, said alkyl, alkenyl,alkynyl and cycloalkyl optionally being substituted with at least onehalogen.
 3. The method according to claim 1, wherein each R² isindependently selected from halogen, R⁵O(CH₂)_(q), and R⁵S(CH₂)_(q). 4.The method according to claim 2, wherein each R² is independentlyselected from halogen, R⁵O(CH₂)_(q), and R⁵S(CH₂)_(q).
 5. The methodaccording to claim 1, wherein R³ is R⁶R⁷N(CH₂)_(q).
 6. The methodaccording to claim 2, wherein R³ is R⁶R⁷N(CH₂)_(q).
 7. The methodaccording to claim 3, wherein R³ is R⁶R⁷N(CH₂)_(q).
 8. The methodaccording to claim 4, wherein R³ is R⁶R⁷N(CH₂)_(q).
 9. The methodaccording to claim 1, wherein both R⁶ and R⁷ are H.
 10. The methodaccording to claim 5, wherein both R⁶ and R⁷ are H.
 11. The methodaccording to claim 1, wherein m is an integer of from 0 to
 2. 12. Themethod according to claim 1, wherein n is 0 or
 1. 13. The methodaccording to claim 1, wherein p is
 0. 14. The method according to claim1, wherein X is NH.
 15. The method according to claim 1, wherein Y isCH₂.
 16. The method according to claim 14, wherein Y is CH₂.
 17. Themethod according to claim 1, wherein each R¹ is independently selectedfrom halogen and C1-C6 alkyl, said alkyl optionally being substitutedwith at least one halogen; each R² is independently selected fromhalogen and R⁵O; R³ is NH₂; R⁵ is C1-C6 alkyl; X is NH; Y is CH₂; m isan integer of from 0 to 2; n is 0 or 1; and p is
 0. 18. The methodaccording to claim 1, wherein the compound of formula (I) is selectedfromN²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;N²-(3-chloro-4-methylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;6-((4-phenylpiperazin-1-yl)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine;N²-phenyl-6-((4-phenylpiperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;and6-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-N²-phenyl-1,3,5-triazine-2,4-diamine;or a pharmaceutically acceptable salt thereof.
 19. The method accordingto claim 1, wherein the disorder or condition is selected from diabetes,stroke and lung fibrosis.
 20. A pharmaceutical composition comprising acompound selected fromN²-(3,4-dimethylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;N²-(3-chloro-4-methylphenyl)-6-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;6-((4-phenylpiperazin-1-yl)methyl)-N²-(p-tolyl)-1,3,5-triazine-2,4-diamine;N²-phenyl-6-((4-phenylpiperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine;and6-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-N²-phenyl-1,3,5-triazine-2,4-diamine;or a pharmaceutically acceptable salt thereof, and optionally at leastone pharmaceutically acceptable excipient.
 21. The method according toclaim 1, wherein the disorder or condition is diabetes.
 22. The methodaccording to claim 1, wherein the disorder or condition is stroke. 23.The method according to claim 1, wherein the disorder or condition islung fibrosis.